Some of the hydroxy N-substituted-2-aminotetralins, such as (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol (also known as rotigotine), 5-hydroxy-dipropylaminotetralin (5-OH-DPAT), 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT), exhibit agonist-like activity through, among other receptors, dopamine and serotonin receptors distributed in various body tissues and address various diseases, particularly central nervous system (CNS) disorders. However, these compounds are prone to poor absorption and significant pre-systemic inactivation limiting their oral utility.
Dopamine is an essential neurotransmitter of the central nervous system. The activity of dopamine is mediated via binding to multiple different dopamine receptors. These receptors can be sorted by their morphology and their manner of signal transduction into classes “D1-like” (D1 and D5) as well as “D2-like” (D2, D3 and D4 receptors). The D3 receptor was first cloned by Sokoloff (Nature 347, 1990, 146) and is especially expressed in the limbic system, in which emotional and cognitive processes are controlled. It is also expressed although somewhat less pronounced in the striatal motor tissue where it serves the purpose of fine regulation of movement processes (Joyce, Pharmacol. Ther 90, 2001, 231-259). Recently, the D3 receptor has been considered a promising target for the development of active agents for the treatment of different psychiatric and motor diseases.
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand. The serotonin receptors modulate the release of many neurotransmitters, including glutamate, gamma amino butyric acid (GABA), dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. The serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. The serotonin receptors are the target of a variety of pharmaceuticals, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin. The 5-HT1A receptor is the most widespread of all the 5-HT receptors. In the central nervous system, 5-HT1A receptors exist in the cerebral cortex, hippocampus, septum, amygdala, and raphe nucleus in high densities. Low amounts also exist in the basal ganglia and thalamus. The 5-HT1A receptor is thought to be involved in neuro-modulation.
The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT7 receptor is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. The 5-HT7 receptor plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract. The highest 5-HT7 receptor densities are in the thalamus and hypothalamus, and it is present at higher densities also in the hippocampus and cortex. The 5-HT7 receptor is involved in thermoregulation, circadian rhythm, learning and memory, and sleep. It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression and this receptor gene is a candidate locus for involvement in autistic disorder and other neuropsychiatric disorders.
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription. Dopamine agonists directly stimulate the receptors in nerves in the brain that normally would be stimulated by dopamine. Unlike levodopa, a dopamine agonist is not changed (converted) into dopamine when it enters the body, but it behaves like dopamine.
Parkinson's disease occurs as a result of a chronic, progressive degeneration of neurons, the cause of which has not yet been completely understood. It is clinically manifested in the form of the cardinal symptoms of resting tremors, rigidity, bradykinesia and postural instability.
Dopamine agonists may be used in the early stages of Parkinson's disease to reduce symptoms. This approach is often effective in people who have been newly diagnosed with the disease (especially those younger than 60), because it can delay the need for levodopa and thus postpone the motor fluctuations that may occur with long-term levodopa therapy.
A dopamine agonist may be added to treatment with a dopaminergic agent such as levodopa in the later stages of Parkinson's disease when levodopa no longer is able to adequately control symptoms on its own, and increasing the dose to provide adequate control of symptoms would cause excessive side effects.
Typically, patients with Parkinson's disease only develop the motor disturbances once approximately 70% to 80% of the dopaminergic neurons in the substantia nigra (SN) have been irreversibly damaged. Generally, the therapy of Parkinson disease normally is initiated with the onset of symptoms such as bradykinesis, resting tremors, rigidity, postural instability, etc.; however, at this point in time the chances of a therapy with lasting effects are minimal. Therefore, it is desirable to commence therapy as early as possible for prophylactic or preventative purposes.
D3 agonists in particular have neuroprotective potential for the treatment and prophylaxis of neurodegenerative disorders (Pulvirenti et al., Trends Pharmacol. Sci. 23, 2002, 151-153; Joyce, Pharmacol. Ther. 90, 2001, 231-259; EP Patent No. 0 988 296; PCT Patent Application Publication Nos. WO 2003/029233 and WO 1993/023035).
D3 agonists could also represent valuable therapeutics for the treatment or prophylaxis of different types of depression, in particular endogenous monophasic depression (“major depression”), pain, anxiety disorders, sexual dysfunctions, especially male erectile dysfunction or female sexual disorder or SSRI induced sexual dysfunction, glaucoma, cognitive disorders, restless leg syndrome, especially moderate to severe restless leg syndrome, restless limb disorder, neurodevelopmental type disorder, attention deficit hyperactivity syndrome (ADHS) or attention deficit hyperactivity disorder (ADHD), hyperkinetic disorder, obsessive compulsive disorder, impulsive disorder, hyperprolactinemia, hyperprolactinoma, eating disorders, neurogenerative disorder, Parkinson-associated movement disorders, dopa and neuroleptic induced/sensitive movement disorders, e.g., akathisia, rigor, dystonia and dyskinesia, as well as cocaine, alcohol, opiate and nicotine addiction, galactorrhea, ovarian hyperstimulation disorder, acromegaly and Parkinson-associated movement disorders, e.g., rigor, dystonia and dyskinesia; L-dopa-induced disorders, idiopathic dystonia, in particular Segawa syndrome, neuroleptic-induced (tardive) dyskinesia, dystonia and akathisia, as well as Parkinson plus syndrome.
2-aminotetratlin derivatives are compounds that are similar in structure to dopamine, likely underlying their pharmacology. Class of compounds with a high affinity for, e.g., D2 “like” and 5HT1A and 5HT7 receptors are the hydroxy N-substituted-2-aminotetralins, e.g. 5-OH-DPAT, (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol (also known as rotigotine or N-0437, hereinafter “rotigotine”), 7-OH-DPAT, and 5,6-dihydroxy-DPAT. Due to amphipathic (having both acidic and basic functionalities) nature of these molecules they have potential to ionize at physiological pHs; therefore, these compounds are prone to issues related to their existence as highly charged species such as zwitterions and lack of sufficient unionized fraction at pHs encountered in the gastrointestinal tract when these compounds are given orally for absorption.
Preclinical data (Swart and Zeeuw, Pharmazie (1992), 47, 613-615) show that hydroxy N-substituted-2-aminotetralins, such as rotigotine, display zero to limited activity upon oral administration. A major disadvantage of the hydroxy N-substituted-2-aminotetralin is that they undergo considerable inactivation by glucuronidation in the gut and the liver, and have insignificant or inappreciable amounts of these compounds existing in the unionized form at pHs encountered in the gastrointestinal tract. One of the strategies to circumvent the problem of low oral bioavailability of the hydroxy N-substituted-2-aminotetralins is to search for suitable bioreversible derivatives.
For efficacy of one such hydroxy N-substituted-2-aminotetralin, rotigotine, maximum steady state levels, Css-max, greater than 0.1 ng/ml of rotigotine, are desired for effective therapy. Importantly, however, to date the oral effectiveness of rotigotine has been elusive, due to a distinct first-pass effect. The bioavailability of N-0923, an enantiomer of rotigotine, after oral administration when tested in animal model was merely about 0.5% (Swart and Zeeuw, Pharmazie (1992), 47, 613-615). Therefore, rotigotine has been previously administered to patients mainly by transdermal delivery methods (see, e.g., U.S. Pat. Nos. 8,617,591; 8,246,979; and 6,929,801; PCT Application Publication Nos. WO 1994/07468 and WO 1999/49852). Other non-oral approaches have also been reported for delivery of rotigotine, such as iontophoretic transdermal (U.S. Pat. No. 7,632,859), intranasal (U.S. Pat. No. 7,683,040), transmucosal (U.S. Application Publication No. 2008/0274061), gingival (U.S. Pat. No. 8,647,314), sublingual, and injectable (U.S. Pat. Nos. 7,309,497 and 8,604,076).
A viable oral dosage form with adequate bioavailability of rotigotine would be desirable for necessary therapeutic applications of such an agent and is expected to be more patient friendly than non-oral forms.
Prodrug or a bioreversible derivatization approach to improve oral bioavailability of drugs prone to first pass inactivation has been reported. (Stella V. J., Charman, W. N. A. and Naringrekar V. H.; Drugs (1985), 29, 455-473). Rodenhuis et. al. (Chapter 6, Neuropharmacological Evaluation of a New Dopaminergic Prodrug with Anti-Parkinsonian Potential, 97-106, 2000—in preparation) have reported data on bioactivity in an animal model of a pharmacophore equivalent, a di-hydro derivative of analogue of 5-OH DPAT, in an attempt to provide oral options for these agents. Specific approaches to improve oral bioactivity of rotigotine via carbamate [den Daas et. al, J. Pharm Pharmacol (1991), 43(1), 11-16] and ester [den Daas et. al., Naunyn Schmiedebergs, Arch Pharmacol (1990), 341(3), 186-191] prodrugs have been attempted in preclinical models; however, identification of specific bioreversible derivatives or compositions, or dosage forms or methods of achieving safe and effective levels of these agents after oral administration, especially rotigotine, in humans still remain an unmet need.
Moreover, the bioreversibility of any prodrug/derivative needs to be managed to get adequate and sustained levels of the drug derived from prodrug in vivo without adding any safety issues associated with the prodrug or its metabolite. Such safety issues will probably be related to the safety of the prodrug entity itself and its bioreversion rate to the parent drug in vivo. A rapid bioreversion rate may be desirable from a safety and efficacy standpoint, but too rapid bioreversion rate may allow the drug to become available in the absorption/distribution pathway too rapidly leading to substantial deactivation of the drug. Therefore, in addition to overcoming absorption challenges with bioreversible hydroxy N-substituted-2-aminotetralin derivative, an adequate bio-reversion rate into the parent drug remain an important design element in prodrug/bioreversible derivative design and is of particular challenge with hydroxy N-substituted-2-aminotetralin compounds due to their being a ready substrate for fast inactivation.
Approaches to date have failed to disclose any specific bioreversible derivative, its compositions, dosage forms and/or methods of use that would be particularly useful in overcoming poor aqueous intrinsic solubility and/or oral delivery/absorption challenges associated with such as bioreversible derivatives.
Therefore, attaining adequate oral bioavailability of hydroxy N-substituted-2-aminotetralins, such as rotigotine, remains a challenge and an unmet need for such compounds. No known approaches including a prodrug/bioreversible derivatives approach to date have been able to successfully deliver orally to attain therapeutically meaningful levels of these important agents.
Thus, there remains a need for an orally bioavailable composition and dosage form that enables safe and efficacious levels of hydroxy N-substituted-2-aminotetralin.